Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Effects of Bcl-2 Overexpressing on the Apoptotic Cell Death Induced by HDAC Inhibitors in Human Leukemic U937 Cells

HDAC 저해제에 의한 인체 백혈병 U937 세포의 apoptosis 유발에 미치는 Bcl-2의 영향

  • Lee, In-Hyuk (Departments of Anatomy, Dongeui University College of Oriental Medicine) ;
  • Hur, Man-Gyu (Departments of Internal Medicine, Dongeui University College of Oriental Medicine) ;
  • Park, Dong-Il (Departments of Internal Medicine, Dongeui University College of Oriental Medicine) ;
  • Choi, Byung-Tae (Departments of Anatomy, Dongeui University College of Oriental Medicine) ;
  • Choi, Yung-Hyun (Departments of Biochemistry, Dongeui University College of Oriental Medicine and Department of Biomaterial Control(BK2l Program), Dongeui University Graduate School)
  • 이준혁 (동의대학교 한의학과 해부학교실) ;
  • 허만규 (동의대학교 한의학과 내과학교실) ;
  • 박동일 (동의대학교 한의학과 내과학교실) ;
  • 최병태 (동의대학교 한의학과 해부학교실) ;
  • 최영현 (동의대학교 한의학과 생화학교실 및 동의대학교 대학원 바이오물질제어학과)
  • Published : 2007.04.25
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Abstract

Histone deacetylase (HDAC) is overexpressed in a variety of cancers and is closely correlated with oncogenic factors. HDAC inhibitors such as trichostatin A(TSA) and sodium butyrate (Na-B) have been shown to induce apoptosis in vitro and in vivo in many cancer cells. The anti-apoptotic Bcl-2 protein has the remarkable ability to prevent cell death and Bcl-2 overexpression has been reported to protect against cell death. We previously reported that the apoptotic cell death of human leukemic U937 cells by TSA and Na-B treatment was associated with the down-regulation of Bcl-2 expression and activation of caspases. In the present study, we investigated the effects of Bcl-2 overexpression on the growth inhibition, cell cycle arrest and apoptosis induced by TSA and Na-B in U937 cells. TSA-induced growth inhibition, cell cycle arrest and apoptosis were significantly attenuated in Bcl-2 overexpressing U937/Bcl-2 cells however Na-B did not affected. Induction of apoptosis by TSA was accompanied by down-regulation of Bcl-2 expression, activation of caspase-3, -8 and -9, and degradation of DNA fragmentation factor/inhibitor of caspase-activated DNase, which was blocked by the overexpression of Bcl-2. Collectively, these findings suggest that ectopic expression of Bcl-2 appeared to inhibit TSA-induced apoptosis by interfering with inhibition of Bcl-2 and caspase activation.

본 연구에서는 인체백혈병세포 U937에서 HDAC 저해제에 의한 증식억제, 세포주기 교란 및 apoptosis 유도에 미치는 Bcl-2 유전자의 영향에 관하여 조사하였다. 이를 위하여 U937/vector 및 U937/Bcl-2 세포주를 대상으로 대표적인 HDAC 저해제인 TSA 및 Na-B 처리에 의한 세포 증식 및 생존율에 미치는 영향을 조사한 결과, TSA에 의한 U937 세포의 증식억제 및 생존율의 감소는 Bcl-2의 과발현에 의하여 차단되는 효과를 보였으나, Na-B는 U937/vector 및 U937/Bcl-2세포사이에 큰 변화를 보이지는 않았다. 세포주기 교란효과에서 Na-B는 TSA에 비하여 유의적인 차이를 보이지 못하였으며, 이는 TSA에 의한 apoptosis가 U937/Bcl-2 세포에서는 억제되었으나, Na-B에 의한 apoptosis는 Bcl-2의 과발현에 의하여 차단되지 못한 것과 연관성이 있는 결과였다. 또한 TSA에 의한 apoptosis 유발의 Bcl-2에 의한 차단 효과는 TSA에 의하여 활성화된 caspase의 활성 억제, Bcl-2 발현 자체의 완화 등 apoptosis 조절 인자들의 발현 및 활성 변화에 기인 된 것임을 알 수 있었다.

Keywords

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